Prediction of molecular interaction of Phosphodiesterase 10A inhibition by natural compounds: insights from structure-based screening and molecular dynamics simulations

Phosphodiesterase 10 A (PDE10A) is an enzyme that regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the brain, particularly in the striatum, which plays a critical role in movement control and reward processing. Inhibition of PDE10A can increase cAMP and cGMP levels, improving neuronal signaling and reducing symptoms of neuropsychiatric disorders such as schizophrenia, Huntington's disease, and Parkinson's disease. In this study, a structure-based virtual screening was conducted to identify potential anti-neuropsychiatric disorders compounds from phytoconstituents in the IMPPAT database. The ligands were docked against PDE10A, resulting in 40 compounds with appreciable docking scores. These 40 compounds underwent further ADMET predictions and drug likeliness, resulting in five potential compounds. Finally, based on the specific interactions, two compounds (Colladonin and Isopongachromene), were subjected to molecular dynamics (MD) simulation and MM-PBSA studies. The MM-PBSA analysis validated and captured the intermolecular interactions, indicating that Colladonin and Isopongachromene had appreciable binding affinities of -155.60 kJ.mol(-1) and -108.28 kJ.mol(-1), respectively and were promising candidates against neuropsychiatric disorders, targeting PDE10A. Overall, this study provides insight into the potential of PDE10A inhibitors as therapeutic agents for treating neuropsychiatric disorders, and Colladonin and Isopongachromene are promising compounds for further development.